Breakthrough Clinical Results
Akeso's ivonescimab, a PD-1/VEGF bispecific antibody, has been granted Breakthrough Therapy Designation (BTD) by China's National Medical Products Administration (NMPA) for first-line treatment of triple-negative breast cancer (TNBC) in combination with chemotherapy. This marks the fourth BTD for ivonescimab, with previous designations including NSCLC treatments. The ongoing Phase III clinical trial (HARMONi-BC1/AK112-308) is expected to be expedited due to this designation. Ivonescimab has demonstrated substantial clinical benefits across multiple cancer types and is currently being evaluated in 14 Phase III clinical trials worldwide.
Key Highlights
- Ivonescimab granted Breakthrough Therapy Designation (BTD) in China for first-line treatment of triple-negative breast cancer (TNBC).
- This is the fourth BTD received by ivonescimab.
- Phase III clinical trial (HARMONi-BC1/AK112-308) for ivonescimab in combination with chemotherapy is ongoing.
- Ivonescimab has been approved for marketing in China for NSCLC resistant to EGFR-TKI therapy and first-line treatment of PD-L1-positive NSCLC.
Incidence and Prevalence
Latest Global Estimates of Breast Cancer Incidence and Prevalence
Breast cancer is the most commonly diagnosed cancer worldwide and one of the leading causes of cancer death according to 2024 data. It ranks first in incidence and second in deaths worldwide, with alarmingly rising mortality rates.
Global Incidence
The incidence of breast cancer is increasing on average by about 1% per year in industrialized countries and at a greater rate in developing countries. In 2019, the age-standardized incidence rate (ASIR) of breast cancer in women worldwide was 45.86 and is projected to reach 48.09 by 2030.
According to 2022 data, there were close to 20 million new cases of cancer globally, with female breast cancer accounting for 11.6% of all cancers. The estimated annual percentage change (EAPC) in breast cancer incidence globally was 0.36 from 1990 to 2019 and is expected to increase to 0.44 from 2020 to 2030.
Regional Variations
Incidence rates in 2022 varied four-fold to five-fold across world regions: - Among women: from over 400 in Australia/New Zealand (410.5 per 100,000) to close to 100 in South-Central Asia (103.3 per 100,000) - Breast cancer incidence ranges from 27/100,000 (Central-East Asia and Africa) to 85-94/100,000 (Australia, North America and Western Europe)
In China (2008-2012), female breast cancer incidence was 42.67/100,000, with higher rates in urban areas (51.85/100,000) than rural areas (28.29/100,000).
A US study (2010-2015) found the annual incidence rate of breast cancers was 31.3 per 100,000 in non-Hispanic White women, higher than other racial/ethnic groups.
Projected Trends
The number of women diagnosed with breast cancer is projected to rise to approximately 3 million annual cases by 2050 from approximately 2 million in 2022. The number of breast cancer-related deaths is projected to rise to over 1 million by 2050 from approximately 660,000 in 2022.
The largest increases in both incidence and mortality will be in less developed regions of the world. The fastest increase in burden is anticipated in Central sub-Saharan Africa, with the Solomon Islands and China projected to experience significant increases.
Survival Rates
The prognosis of female breast cancer patients is generally favorable, with 5-year relative survival rates above 80% in most regions. The global survival rates in women with breast cancer were: - 1-year: 0.92 (95% CI, 0.90-0.94) - 3-year: 0.75 (95% CI, 0.71-0.79) - 5-year: 0.73 (95% CI, 0.71-0.75) - 10-year: 0.61% (95% CI, 0.54-0.67)
The highest age-standardized 5-year relative survival rate was in the USA (2010-2014) at 90.2%, while the lowest was in India (2010-2014) at 66.1%. North America and Oceania had the best survival, while in Europe, survival was worst in Eastern Europe.
While there has been a steady improvement in female breast cancer survival worldwide, the survival gap between developed and developing countries has remained wide over the past 30 years.
Key Unmet Needs and Target Populations in Breast Cancer
Major Unmet Needs
Triple-negative breast cancer (TNBC) remains a significant unmet need due to the lack of therapeutic targets, making it difficult to treat compared to other breast cancer types. TNBC is intrinsically aggressive with high mitotic indexes and tendency to metastasize to the central nervous system, correlating with poor survival as tumors often relapse following chemo- and radio-therapies.
The biggest challenges in breast cancer treatment are metastasis and drug resistance. Metastasis is described as the fatal hallmark of breast cancer, with current effective therapeutic targets of metastasis still lacking. For patients with advanced or metastatic breast cancer, the survival rate remains low, highlighting the urgent need for new therapies.
Drug resistance represents another critical challenge, with ATP-binding cassette transporters (ABCs) genes contributing to the increased effluent of cell-toxic drugs and subsequent treatment resistance. About 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies.
Target Populations
HER2-low breast cancer patients are a key target population, defined as those with IHC 1+ or IHC 2+/ISH- expression levels. Trastuzumab deruxtecan (T-DXd) has been approved for patients with unresectable or metastatic HER2-low breast cancer after prior chemotherapy.
Triple negative breast cancer (TNBC) patients are targeted for new therapies like Sacituzumab govitecan (SG), which is approved for metastatic TNBC.
Patients with hormone receptor-positive, HER2-negative advanced breast cancer are targeted for palbociclib treatment, while those with HER2-positive metastatic breast cancer who have progressed to third-line treatment represent an area of unmet need.
Patients with bone metastases who are HER2-negative and hormone receptor-positive are being targeted with denosumab in combination with CDK4/6 inhibitors.
Underserved Populations
Low- and middle-income countries (LMIC) represent an underserved population, with predictions that much of the incidence and mortality related to breast cancer will be seen in these populations in the coming decades. Their fragile and ill-prepared healthcare systems need to address breast cancer challenges with limited resources.
Significant disparities exist in stage at presentation as the ability to detect the disease in earlier stages is compromised in LMIC. Access to healthcare and to basic surgical, radiotherapy and systemic care is suboptimal in these regions.
In the United States, underserved women often experience significant delays in diagnosis and treatment, leading to higher mortality rates. The breast cancer mortality rate remains approximately 40% higher among Black and African American women compared to White women.
Emerging Therapeutic Approaches
Immunotherapy, particularly targeting immune checkpoints like programmed death-1 (PD-1), has emerged as a promising approach, though not all patients benefit from these therapies.
Liquid biopsies are being explored to overcome limitations of traditional tumor biopsies, which are invasive and may not reflect tumor heterogeneity.
Mitotic kinases like Aurora A, Aurora B, Bub1, and Hec1 are being investigated as novel targets for therapeutic interventions, particularly in relation to epithelial-to-mesenchymal transition (EMT).
Drug used in other indications
Indications for Ivonescimab Beyond Breast Cancer and Their Intervention Models
Non-small Cell Lung Cancer (NSCLC)
Ivonescimab is being extensively evaluated in NSCLC through multiple trial approaches: - First- or second-line monotherapy in patients with advanced immunotherapy-naive NSCLC - Combination therapy with pemetrexed and carboplatin for patients with relapsed advanced or metastatic NSCLC with EGFR variant - Comparative trial against pembrolizumab in patients with PD-L1-positive advanced NSCLC
The HARMONi-5 study evaluated ivonescimab as monotherapy with various dosing schedules: 10 mg/kg every 3 weeks, 20 mg/kg every 2 weeks, 20 mg/kg every 3 weeks, or 30 mg/kg every 3 weeks.
In HARMONi-2, a randomized, double-blind, phase 3 trial across 55 hospitals in China, patients received either 20 mg/kg ivonescimab or 200 mg pembrolizumab intravenously every 3 weeks.
Small Cell Lung Cancer (SCLC)
For extensive-stage SCLC, ivonescimab is being tested as: - Combination therapy with etoposide and carboplatin as first-line treatment - The intervention model includes up to four cycles of combination therapy, followed by ivonescimab as maintenance
Advanced Solid Tumors
A first-in-human, phase 1a study evaluated ivonescimab in patients with advanced solid tumors using: - A dose escalation design (3+3+3) with ivonescimab administered at 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks - Dose expansion at 10 and 20 mg/kg in selected tumor types
Specific Solid Tumors
Efficacy signals have been observed in several specific indications: - Platinum-resistant ovarian cancer (26.3% of patients achieved partial response) - Mismatch repair proficient (pMMR) colorectal cancer - MMR deficient and pMMR endometrial cancer
Intervention Dosing Models
Across the various trials, ivonescimab has been administered using different dosing schedules: - Every 2 weeks (Q2W) dosing: 20 mg/kg - Every 3 weeks (Q3W) dosing: 10 mg/kg, 20 mg/kg, or 30 mg/kg - The maximum tolerated dose (MTD) was determined to be 20 mg/kg every 2 weeks in the phase 1a study
Trial Designs
The clinical development program for ivonescimab includes diverse trial designs: - Randomized, double-blind, placebo-controlled phase 3 trials - Dose escalation studies - Comparative studies against standard of care treatments
In one phase 3 trial for EGFR-mutated NSCLC, ivonescimab plus chemotherapy showed significant improvement in progression-free survival compared to chemotherapy alone (7.1 months vs 4.8 months).
Ivonescimab, a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously, has demonstrated promising results across these indications, with a confirmed objective response rate of 25.5% and disease control rate of 63.8% in its phase 1a study across multiple solid tumors.